Abstract: The thalamus and neocortexare essential for normal sensation, movement, and cognition, and they work in intimate, inextricable association. The thalamus is the origin of virtually all specific information entering the neocortex, and the neocortex in turn sends massive feedback to the thalamus. Specific inhibitory neurons in both the thalamus and neocortex are critical regulators of information flow through the thalamocortical system. The central goal of my proposal is to understand the diverse functions of some of these inhibitory neurons and their synapses.There are four specific aims: 1) To characterize two distinctly different types of neocortical inhibitory intemeurons and their roles in the earliest stages of thalamocortical processing;2) To characterize the roles of these intemeurons in local circuits in the neocortex;3) To test the activity- and state-dependence of inhibitory functions;4) To characterize synaptic connections to, from, and within the thalamic reticular nucleus. We will use transgenic lines of mice to identify and select the neurons of interest, a variety of in vitro methods to recordfrom identified intemeurons, anatomical methods to verify and characterize neuron types, and pharmacological and molecular tools to manipulate cells and synapses. The proposed experiments will provide novel and important insight into the cellular mechanisms of inhibition in the thalamocortical system. This information will be of central importance to our understanding of the mechanisms of sensory, motor, and cognitive processing and their disorders. Description: The cerebral cortex and its partner, the thalamus, are brain regions critical for the most complex and uniquely human behaviors. Abnormalities of inhibitory nerve cells in the cortex and thalamus have been implicated in epilepsy, schizophrenia, anxiety, and other neurological and psychiatric diseases. The experiments proposed here will characterize the normal functions of inhibitory cells, so that their roles in disease can be more rationally evaluated.